CN106324114B - The detection method of bisulfate clopidogrel specific impurities in a kind of compound preparation - Google Patents
The detection method of bisulfate clopidogrel specific impurities in a kind of compound preparation Download PDFInfo
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- CN106324114B CN106324114B CN201510386472.XA CN201510386472A CN106324114B CN 106324114 B CN106324114 B CN 106324114B CN 201510386472 A CN201510386472 A CN 201510386472A CN 106324114 B CN106324114 B CN 106324114B
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Abstract
The invention discloses detection method of the bisulfate clopidogrel in relation to substance specific impurities in a kind of bisulfate clopidogrel aspirin compound preparation, using the related substance of high effective liquid chromatography for measuring compound preparation clopidogrel, especially specific impurities A and B caused by compound preparation.Use octadecyl silane for chromatographic column carrier, mobile phase A is the mixed solvent of organic solvent and ion pair buffer salt (pH2.0~5.0), Mobile phase B is the mixed solvent of methanol and acetonitrile, is eluted according to gradient condition, and the structural analysis of specific impurities is carried out using LC/MS/MS.The method of the present invention detection sensitivity is high as the result is shown, precision is good, strong for specific impurities specificity in bisulfate clopidogrel and aspirin compound preparation, is the effective ways of such compound preparation quality of strict control.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are related to a kind of detection method of the related substance of pharmaceutical preparation, and in particular to
A kind of related substance of acute coronary syndrome medicine bisulfate clopidogrel aspirin compound preparation clopidogrel is specific miscellaneous
The detection method of matter.
Background technique
Acute coronary artery syndrome (ACS) be with Coronary Atherosclerotic Plaque rupture or corrode, it is secondary formed completely or
Incomplete occluding thrombus is one group of clinical syndrome on case basis.Including the ST sections of property raised myocardial infarctions, acute ST sections non-
The property raised myocardial infarction and unstable angina.
Pharmaceutical research is shown: platelet activation is in the Development process of ACS, and through drug or PTCA or and STENTS ischemic
Key player is play in the recurrence of event, has become the basis for the treatment of ACS.In past 20 years, Antiplatelet therapy is
Through become ACS after secondary prevention conventional means, Present clinical practice in 75% or more patient discharge when receive dual anti-blood
Platelet treatment.Aspirin and clopidogrel all have antiplatelet aggregative activity, and the two mechanism is different, action compensating, the two
Duplex therapy be most common Antiplatelet therapy strategy.For Non-ST elevation coronary syndrome (including shakiness
Qualitative angina pectoris or Non-Q-wave myocardial infarction) and the ST sections of property raised acute coronary syndromes treatment, it is athero- hard with prevention of arterial
Change Cardioversion to occur again.
Bisulfate clopidogrel aspirin compound preparation belongs to the compound preparation of fixed dosage composition, and the current country there is no
Listing product.For the patient for needing Long-term taking medicine, compound preparation has better biddability and more preferably therapeutic effect, therefore opens
The compound is sent out to a kind of curative for effect, safe ready is provided, the ACS therapeutic agent of Small side effects is particularly significant.
The existing national drug standards, import registered standard and document report, relate generally to bisulfate clopidogrel or Ah
Take charge of the method for quality control of a woods single component.But bisulfate clopidogrel aspirin compound preparation is in wet, hot, sour, alkali, oxygen
Unstable under the conditions of change etc., impurity comes not only from raw material itself, the specific impurities for also having the two interaction to generate.It should
Specific impurities growth is extremely rapid, and verifies without pathology toxicology, is an important hidden danger of compound preparation safe medication.But
It is that there is not been reported for the research about compound preparation in relation to substance specific impurities at present.Therefore, the related substance of research compound preparation
The detection method of specific impurities formulates stringent quality control standard, for guaranteeing safety, validity and the matter of drug quality
Amount controllability is very important.
Summary of the invention
Detection method of the bisulfate clopidogrel aspirin in relation to substance specific impurities is not disclosed in view of the prior art,
The purpose of the present invention is to provide a kind of bisulfate clopidogrels with aspirin compound preparation in relation to the inspection of substance specific impurities
Survey method, compound preparation include: tablet, capsule, dispersible tablet, granule, micropill preparation, pill, film, oral liquid
With controlled release agent etc..The analysis method can be used for the preparation process and final production of bisulfate clopidogrel aspirin compound preparation
The quality of product controls, particularly for the detection of specific impurities in compound preparation.
To achieve the above object, this invention takes following technical schemes:
Detection method in relation to substance specific impurities in a kind of bisulfate clopidogrel and aspirin compound preparation, use
High performance liquid chromatography measures the specific impurities that related substance therein, the especially compound preparation generate.
It uses octadecyl silane for chromatographic column carrier, is with buffer salt-organic solvent mixed phase and organic phase
Mobile phase is eluted according to gradient condition.Detection wavelength is 220nm, sampling volume 10 μ L, flow velocity 1.0ml/min, column temperature
It is 30~40 DEG C.Related substance is calculated so that the principal component Self-control method of correction factor is not added.
Organic phase described in the method for the present invention is selected from the mixture of acetonitrile, methanol or methanol and acetonitrile, preferably acetonitrile and methanol
Mixture, mixed proportion be acetonitrile-methanol=96:4~99:1.Buffer salt is phosphorus in buffer salt-organic solvent mixed phase
Phthalate buffer, acetate buffer or ion-pairing agent, preferred ion is to reagent.Ion pair buffer concentration is 0.02mol/
L~0.14mol/L, pH range are 2.0~5.0, and preferably pH is 2.5.Organic solvent is selected from buffer salt-organic solvent mixed phase
The ratio of methanol or acetonitrile, preferably methanol, ion pair buffer salt and methanol is 96:4~99:1.
Gradient elution program is as shown in table 1, and wherein A phase is ion pair buffer-methanol=96:4~99:1, B Xiang Weiyi
Nitrile-methanol=96:4~99:1.
1 gradient elution program of table
R*=11~22min；X*=90%~85%.
Sample mixed solvent is configured described in the method for the present invention are as follows: mobile phase A phase-acetonitrile=40:60.It is measured described in this method
The preparation method of sample are as follows: by bisulfate clopidogrel aspirin compound preparation mixed solvent ultrasonic dissolution.It is preferred super
The control of sound temperature is 15 DEG C~25 DEG C.
Compared with the prior art and analysis method, bisulfate clopidogrel aspirin compound preparation chlorine of the present invention
Pyrrole Gray has the following advantages that in relation to the detection method of substance specific impurities and marked improvement:
It (1) can be by known impurities (2S)-(2 chlorphenyl)-(6,7- dihydro-thiophene simultaneously [3,2-c] pyridine -5-4H base)-second
Sour (European Pharmacopoeia clopidogrel impurity A) and aspirin main peak and 2 hydroxybenzoic acid (Chinese Pharmacopoeia salicylic acid) effectively divide
From；
(2) methyl (2S)-(2 chlorphenyl) [4,7- dihydro-thiophene simultaneously [2,3-c] pyridine -6-5H base]-acetic acid (European Pharmacopoeia
Clopidogrel impurity B) increase with bisulfate clopidogrel separating degree, it separates more complete；
(3) (retention time is respectively bisulfate clopidogrel with two specific impurities in aspirin compound preparation
25.4min and 26.7min) it efficiently separates, and separated with aspirin and 2 hydroxybenzoic acid (Chinese Pharmacopoeia salicylic acid) good
It is good.
The method of the present invention detection sensitivity is high, and precision is good, in bisulfate clopidogrel aspirin compound preparation
Specific impurities specificity it is very strong, be the effective ways of such compound preparation quality of strict control.Meanwhile in conjunction with the embodiments in 6
Structural analysis to specific impurities, it may be considered that the specific impurities in controlled syntheses compound preparation mention for preparation safety Journal of Sex Research
For according further to.
Detailed description of the invention
Fig. 1 is that the related substance of 1 bisulfate clopidogrel aspirin compound preparation of embodiment detects chromatogram；
Fig. 2 is the related blanc auxiliary material figure of 1 bisulfate clopidogrel aspirin compound preparation of embodiment；
Fig. 3 is 2 bisulfate clopidogrel aspirin compound preparation alkali failure test chromatogram of embodiment；
Fig. 4 is 60 DEG C of 3 bisulfate clopidogrel aspirin composite tablet of embodiment and places 10 days related substance detection colors
Spectrogram；
Fig. 5 is that 4 bisulfate clopidogrel aspirin composite tablet of embodiment accelerates 3 months related substances to detect chromatography
Figure；
Fig. 6 is that 6 bisulfate clopidogrel aspirin compound preparation of embodiment is placed 15 days under the conditions of RH90% ± 5%
LC/MS/MS figure.
Specific embodiment
The following examples will make the present invention more specifically to explain, but the present invention is not limited only to these implementations
Example, these same embodiments are not also limit the invention in any way.
Embodiment 1
Instrument and condition: using C18 column, and mobile phase A is mutually that (adjust pH value is methanol -0.05mol/L sodium pentanesulfonate
2.5)=3:97, Mobile phase B are methanol-acetonitrile=3:97, and gradient elution program is as shown in table 2:
2 gradient elution program of table
Detection wavelength is 220nm, and flow velocity 1.0ml/min, column temperature is 35 DEG C.
It is appropriate that precision weighs bisulfate clopidogrel aspirin compound preparation fine powder, is placed in centrifuge tube, and mixing is added
Solvent (mobile phase A phase-acetonitrile=40:60) is configured in every 1ml the about solution of containing clopidogrel hydrogen sulfate 6.5mg, 15 DEG C~
25 DEG C of temperature controlled ultrasonics, centrifugation, take supernatant to measure, as test solution.Precision measures test solution 1ml, and mixing is added
Solvent (mobile phase A phase-acetonitrile=40:60) is configured in every 1ml the about solution of 6.5 μ g of containing clopidogrel hydrogen sulfate, as right
According to solution.
Bisulfate clopidogrel raw material, aspirin raw material, auxiliary material is separately taken to configure solution according to the above method and survey with condition
It is fixed.The retention time of bisulfate clopidogrel aspirin composition raw material, known impurities and specific impurities is shown in Table 3.
The retention time of 3 bisulfate clopidogrel aspirin composition raw material of table, known impurities and specific impurities
| Peak title | Retention time | Relative retention time |
| Aspirin | 19.9min | 0.464 |
| 2 hydroxybenzoic acid | 23.5min | 0.548 |
| (2S)-(2 chlorphenyl)-(6,7- dihydro-thiophene simultaneously [3,2-c] pyridine -5-4H base)-acetic acid | 22.3min | 0.520 |
| Methyl (2S)-(2 chlorphenyl) [4,7- dihydro-thiophene simultaneously [2,3-c] pyridine -6-5H base]-acetic acid | 45.2min | 1.054 |
| Bisulfate clopidogrel | 42.9min | 1.000 |
| Specific impurities 1 | 25.5min | 0.594 |
| Specific impurities 2 | 26.8min | 0.627 |
Measurement result is shown, outside the impurity detected in sulfuric acid clopidogrel hydrogen raw material, aspirin raw material, hydrogen sulfate chlorine
There is unknown impuritie peak at 25.5min in the chromatogram of pyrrole Gray and aspirin compound preparation, 26.8min, for the compound preparation
Specific impurities, method specificity is good, blank auxiliary not interference measurement.
Embodiment 2
For verify chromatographic condition feasibility, further to compound preparation carried out sour destruction, alkali destruction, Oxidative demage,
High temperature and illumination failure test.
1. acid destroys: taking bisulfate clopidogrel aspirin compound preparation fine powder appropriate, be placed in centrifuge tube, be added
1mol/L hydrochloric acid is appropriate, and mixed solvent (mobile phase A phase-acetonitrile=40:60) is added in right amount, 15~25 DEG C of temperature controlled ultrasonic dissolutions,
Supernatant is taken after centrifugation, places 2h in 60 DEG C of baking ovens, destroys solution as acid.
2. alkali destroys: taking bisulfate clopidogrel aspirin compound preparation fine powder appropriate, be placed in centrifuge tube, be added
1mol/L Sodium hydroxide q.s. are added mixed solvent (mobile phase A phase-acetonitrile=40:60) and are diluted to sample concentration, and 15~25 DEG C
Temperature controlled ultrasonic dissolution, takes supernatant, places 2h in 60 DEG C of baking ovens after centrifugation, destroy solution as alkali.
3. Oxidative demage: taking bisulfate clopidogrel aspirin compound preparation fine powder appropriate, be placed in centrifuge tube, be added
30% hydrogenperoxide steam generator is appropriate, and mixed solvent (mobile phase A phase-acetonitrile=40:60) is added and is diluted to sample concentration, and 15~25
The dissolution of DEG C temperature controlled ultrasonic, takes supernatant after centrifugation, is placed at room temperature for 1h, as Oxidative demage solution.
4. high temperature: taking bisulfate clopidogrel aspirin compound preparation fine powder appropriate, be placed in centrifuge tube, be added
Mixed solvent (mobile phase A phase-acetonitrile=40:60), 15~25 DEG C of temperature controlled ultrasonics take supernatant, put in 60 DEG C of baking ovens after centrifugation
4h is set, as high temperature solution.
5 illumination destroy: taking bisulfate clopidogrel aspirin compound preparation fine powder appropriate, are placed in centrifuge tube, are added
Mixed solvent (mobile phase A phase-acetonitrile=40:60), 15~25 DEG C of temperature controlled ultrasonics take supernatant, 4000LX ± 500LX after centrifugation
It is irradiated for 24 hours under strong light, as photo damage solution.
Above-mentioned each solution is measured according to the measuring method precision of embodiment 1 to be measured.Measurement result is shown: hydrogen sulfate chlorine
Pyrrole Gray and aspirin compound preparation are miscellaneous after sour destruction, alkali destruction, Oxidative demage, heat damage and illumination failure test
Matter increased.Especially under alkali failure test, specific impurities peak is obviously increased at 25.4min, 26.7min.Each destroy produces
Object impurity peaks are kept completely separate with main peak, which has good selectivity.
Embodiment 3
In order to further verify the applicability of chromatographic condition, and confirm in bisulfate clopidogrel aspirin compound preparation
Specific impurities community, take bisulfate clopidogrel aspirin composite tablet and bisulfate clopidogrel Ah Si respectively
Woods compound capsule is placed 10 days under ± 5% super-humid conditions of RH90%, 60 DEG C of hot conditions and 4000 ± 500LX intense light conditions,
It is measured according to the measuring method of embodiment 1.Measurement result is as shown in table 4.
4 different dosage forms bisulfate clopidogrel aspirin compound preparation impurity determination result of table
The results show that can be detected in different dosage forms bisulfate clopidogrel aspirin compound preparation 25.4min,
26.7min specific impurities；10 are placed in ± 5% super-humid conditions of RH90%, 60 DEG C of hot conditions and 4000 ± 500LX intense light conditions
It, specific impurities obviously increase.The applicability of chromatographic condition is further demonstrated, and the matter of the compound preparation can be effectively controlled
Amount.
Embodiment 4
In order to investigate the growth of the specific impurities in bisulfate clopidogrel aspirin compound preparation during storage
Situation takes bisulfate clopidogrel aspirin composite tablet in long-term conditions (60% ± 5%, 25 DEG C ± 2 DEG C of temperature), accelerates
It places 3 months under condition (relative humidity is 75% ± 5%, 40 DEG C ± 2 DEG C of temperature), is carried out according to the measuring method of embodiment 1
Measurement.Measurement result is as shown in table 5.
The different placement condition bisulfate clopidogrel aspirin compound preparation specific impurities measurement results of table 5
As the result is shown: bisulfate clopidogrel aspirin compound preparation stability is poor, is easy to produce under wet heat condition
Raw specific impurities, newly-generated specific impurities are verified without toxicology, have certain hidden danger in terms of safe medication.It is therefore proposed that
Compound preparation should seal, and be placed at 25 DEG C or less dryings and save.
Embodiment 5
In order to investigate different ions to the mixed proportion and gradient condition of buffer salt and methanol in concentration, mobile phase A phase
Change, in bisulfate clopidogrel aspirin compound preparation specific impurities detect influence, to measurement side in embodiment 1
Method is adjusted.
The selection of 5.1 gradient conditions: gradient condition in embodiment 1 is adjusted by following gradient condition tables, Qi Tase
Spectral condition remains unchanged.60 DEG C of the bisulfate clopidogrel aspirin composite tablet samples for placing 10 days are taken, compound system is measured
The related substance of agent.
6 gradient elution program table of table
R* is respectively 5min, 10min and 23min.
Separating effect see the table below:
7 separating effect of table
The mixed proportion of 5.2 mobile phase A phase buffer salts and methanol: by the ratio of methanol in embodiment 1 and ion pair buffer
Example is changed to pure water phase and 5:95 respectively, and other chromatographic conditions are the same as described in embodiment 1.Take bisulfate clopidogrel Ah Si
The sample of 60 DEG C of woods composite tablet placements 10 days, measures the related substance of compound preparation, separating effect is as follows:
8 separating effect of table
| Mobile phase A | Separating effect |
| Pure water phase | Gradient elution unstability of base line |
| Methanol-ion pair buffer=5:95 | Two specific impurities can not be kept completely separate |
5.3 ion pair concentration: being changed to 0.01mol/L and 0.15mol/L to buffer concentration for 1 intermediate ion of embodiment,
Other chromatographic conditions are the same as described in embodiment 1.Take 60 DEG C of the bisulfate clopidogrel aspirin composite tablet samples for placing 10 days
Product measure the related substance of compound preparation, and separating resulting see the table below:
9 separating effect of table
The result shows that: gradient elution first step R* should be controlled in the range of 10~22min, in mobile phase A methanol with from
Son should control in the range of 96:4~99:1 the ratio of buffer salt, and the concentration of ion-pairing agent should be controlled in 0.02mol/L
In the range of~0.14mol/L.
Embodiment 6
In order to further determine the structure of 25.4min and 26.7min unknown impuritie, using method associated with liquid chromatography mass spectrometric,
The molecular weight for measuring specific impurities, to speculate the possible structure of specific impurities.
Liquid phase part uses C18 column, and mobile phase A is mutually that (second acid for adjusting pH value is methanol -0.0025mol/L ammonium acetate
4.0)=6:94, Mobile phase B are methanol-acetonitrile=6:94.
Condition of gradient elution is as follows:
10 condition of gradient elution of table
Flow velocity is 1.0ml/min, and Detection wavelength 230nm, column temperature is 35 DEG C.
Mass spectrometry parameters are as follows: atomization gas pressure is 30psi；Dry gas stream speed is 8.0ml/min；Dry temperature degree is 350
℃；Scanning range is 50-1000m/z, and the scanning frequency is 5s；Detection mode is positive ion mode level-one, second level scanning.
Bisulfate clopidogrel aspirin compound preparation is placed 15 days under the conditions of RH90% ± 5%, takes the compound
Preparation fine powder is appropriate, is placed in centrifuge tube, is added mixed solvent (mobile phase A phase-acetonitrile=40:60), and 15~25 DEG C of temperature controls are super
Sound dissolution, takes supernatant to measure after centrifugation.
As the result is shown: under the conditions of the LC/MS, former 25.4min impurity peaks become 27min, and former 26.7min impurity peaks become
34.0min.(1) it is composed according to mass spectrum level-one and speculates that 25.4min special impurities structure may are as follows:
The results show that its second level spectrum fragment is 590.9, possible lytic pathway are as follows:
(2) it is composed according to mass spectrum level-one and speculates that 26.8min special impurities structure may are as follows:
It is 335.7,182.7,154.7 that its second level, which composes fragment, possible lytic pathway are as follows:
。
Claims (5)
1. a kind of bisulfate clopidogrel and bisulfate clopidogrel in aspirin compound preparation be in relation to the detection method of substance,
It is characterized in that, the related substance is compound preparation specific impurities A, B；Its karyoplasmic ratio is respectively 607 and 337；The detection
Method uses high performance liquid chromatography, and chromatographic condition is as follows:
Chromatographic column: octadecyl silane column；
Mobile phase: A phase is ion pair buffer salt-methanol=96:4~99:1；
B phase is acetonitrile-methanol=96:4~99:1；
Condition of gradient elution are as follows:
R*=11~22min；X*=90%~85%；
Detector: UV detector.
2. detection method according to claim 1, which is characterized in that the ion-pairing agent are as follows: sodium pentanesulfonate, heptane
The mixture of sodium sulfonate or both, mixed proportion are 40:60~60:40.
3. detection method according to claim 1 or 2, it is characterised in that the ion-pairing agent concentration is 0.02mol/L
~0.14mol/L.
4. -2 described in any item detection methods according to claim 1, which is characterized in that the pH of the buffer salt solution of the A phase
It is 2.0~5.0.
5. detection method according to claim 4, which is characterized in that the pH of the buffer salt solution of the A phase is 2.5.
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| CN111812223B (en) * | 2020-06-01 | 2022-08-16 | 南京品生医学检验实验室有限公司 | Method for detecting antiplatelet drugs in plasma by ultra-high performance liquid chromatography tandem mass spectrometry technology |
| CN115326942B (en) * | 2022-02-22 | 2023-12-22 | 苏州正济医药研究有限公司 | Analysis method for measuring thiophene tosylate |
| CN115327003B (en) * | 2022-08-12 | 2024-03-12 | 成都施贝康生物医药科技有限公司 | Method for detecting clopidogrel oxide related substances |
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| CN101591346B (en) * | 2009-07-03 | 2014-10-29 | 北京华禧联合科技发展有限公司 | Novel method for synthesizing related substance B of clopidogrel bisulfate |
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